tbuckley/cabot-search huggingface dataset:
Abstract PR003: Apoptotic DNase DFFB mediates stress-induced mutagenesis
Authors: August F. Williams, David A.G. Gervasio, Claire E. Turkal, Mehrshad Hairani, Michael X. Wang, Anna E. Stuhlfire, Ariel H. West, Brandon E. Mauch, Michelle H. Paw, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer
Journal: Cancer Research (2023)

Abstract It was recently discovered that actively proliferating and post-mitotic normal human tissues acquire somatic mutations at the same rate. This indicates that somatic mutagenesis is primarily independent of cell proliferation and therefore cannot be based on DNA replication errors. Furthermore, the mutagenic mechanisms which contribute to ubiquitous mutational signatures such as SBS5 remain unknown. It has been hypothesized that tissues accumulate mutations through unknown physiologic processes which contribute to DNA damage but the molecular details remain unknown. These observations have revealed our lack of understanding of the fundamental processes of mutagenesis. Stress-induced mutagenesis has been previously characterized in bacteria which respond to stress by transiently increasing the rate of mutagenesis to promote the emergence of resistance mutations. This phenomenon was recently discovered in human cancer cells but the mechanism is unknown. Here, we present our discovery that cancer cells under drug stress undergo sublethal apoptotic signaling resulting in activation of apoptotic DNase DFFB. DFFB, which canonically acts to fragment chromosomal DNA during apoptosis, induces DNA strand breaks in surviving cancer cells resulting in error prone repair and mutagenesis. In the context of targeted therapy-treated cancer, we found that DFFB is required for acquired resistance to emerge in multiple tumor types. We also found that CD8 T cells induce a similar process in targeted tumor cells which survive. Therefore, sublethal apoptotic signaling may be a general phenomenon which promotes mutagenesis in human cancer. Based on these observations and prior literature showing sublethal apoptotic signaling occurs in normal cells in response to various stress stimuli, we propose that this mechanism may be a previously unknown fundamental mutagenic process which contributes not only to acquired resistance in cancer but also to tumor initiation, aging and other conditions. Citation Format: August F. Williams, David A.G. Gervasio, Claire E. Turkal, Mehrshad Hairani, Michael X. Wang, Anna E. Stuhlfire, Ariel H. West, Brandon E. Mauch, Michelle H. Paw, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer. Apoptotic DNase DFFB mediates stress-induced mutagenesis [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR003.
IDEOM vitiligo work group: an update on our first year
Authors: Nanette B Silverberg, Arnon Cohen, Seemal Desai, Priyanka Francis, Vimala Francis, Jackie Gardner, Carrie Guarino, Isabella Guarino, Victor Huang, David Rosmarin
Journal: British Journal of Dermatology (2023)

Abstract The new Vitiligo Work Group of IDEOM was created in October 2021 and met at the annual IDEOM meetings of 2021 and 2022. The mission of the workgroup is to develop core outcome measures in vitiligo that meet three criteria: to meet the needs of stakeholders of all types, to be validated for clinical trials and studies, and to be used in all age groups of patients. The Vitiligo Work Group met November 2021 and June 2022, yielding a list of 10 potential core domains for voting. Voting was conducted at the Annual Meeting of IDEOM on 18 June 2022. Voting members of IDEOM included 23 dermatologists, 1 rheumatologist, 3 dermatologists and rheumatologists, 11 industry partners, 9 patients, 8 patient association representatives and 15 researchers. Core domains meeting 75% consensus threshold included: health-related quality of life (95·35%), extent of depigmentation (93·632%), treatment satisfaction including treatment burden (92·86%), location (83·67%), colour matching (82·69%) and maintenance of pigmentation (76·47%). Two domains met 50% threshold including primary diagnosis/comorbidities (59·62%) and trajectory of disease/stabilization (57·45%) and one domain, itch, failed to reach a consensus (38·46%). Using an approach of inclusion of stakeholders from all walks of life, six core domains reached a consensus for inclusion, two achieved partial consensus but required revision to break down the elements (e.g. primary diagnosis and comorbidities should be separated) and itch failed to achieve inclusion. The group continues to work on its core domains set using a broad range of stakeholders to produce a practical set of domains that are of importance to all stakeholders.
Ritlecitinib (PF-06651600), an oral JAK3/TEC inhibitor, stabilizes active lesions and promotes re-pigmentation of stable lesions in patients with active nonsegmental vitiligo: results from a phase 2b, randomized, placebo-controlled, dose-ranging study
Authors: Yuji Yamaguchi, Elena Peeva, Ronald Shore, George Han, Lori Ann Cox, Anindita Banerjee, Diamant Thaci, Iltefat Hamzavi, Abigail Sloan, Anand K Ganesan, Khaled Ezzedine
Journal: British Journal of Dermatology (2023)

Abstract Patients with active nonsegmental vitiligo (NSV) may experience active lesions (confetti-like and trichrome lesions) or stable lesions (where lesions may remain unchanged for ∼1 year or more). In a phase 2b trial, the oral JAK3/TEC inhibitor ritlecitinib demonstrated a significant improvement in the Facial-Vitiligo Area Scoring Index at Week 24 for patients with active NSV at 50 mg daily with or without a loading dose (100 or 200 mg daily for 4 weeks). To evaluate the efficacy of ritlecitinib on active vs. stable lesions in patients with active NSV who participated in the phase 2b trial (NCT0371529). Patients were randomized to daily ritlecitinib or placebo for 24 weeks, with or without a 4-week loading dose: 200/50, 100/50, 50, 30, 10 mg, or placebo. Mean percent change from baseline (%CFB) in depigmentation extent (100%, 90%, 75%, 50%, 25%, or 10%) within the lesion at baseline and Week 24 was evaluated centrally using photographs obtained from both active (clinical signs including confetti-like and trichrome lesions) and stable target lesions, other than on the face. The analysis included 317 patients who had active and stable lesions simultaneously among 364 treated patients. Within active lesions, ritlecitinib induced a statistically significant reduction in depigmentation extent [%CFB: 200/50 mg, +0·8 (P = 0·0388); 100/50 mg, −1·7 (P = 0·0035); 30 mg, −1·6 (P = 0·0086)] compared with a progressive increase in depigmentation in the placebo group (%CFB: +5·6). No significant reduction was seen with ritlecitinib 50 mg (+2·8) or 10 mg (+1·4%). Within stable lesions, ritlecitinib showed a statistically significant reduction in depigmentation extent, reflecting re-pigmentation [%CFB: 200/50 mg, −7·2 (P = 0·0045); 100/50 mg, −6·1 (P = 0·0082); 50 mg, −5·9 (P = 0·0134); 30 mg, −8·0 (P = 0·0092)] compared with the placebo group, where %CFB in de-pigmentation increased (%CFB: +0·5). No significant reduction was seen with ritlecitinib 10 mg (−3·3%). The magnitude of the re-pigmentation was numerically greater in stable lesions compared with that in active lesions. In patients with active NSV, ritlecitinib treatment for 24 weeks stabilized active lesions and promoted re-pigmentation of stable lesions.
Abstract PR002: Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals
Authors: Guangbo Chen, Hong Zheng, Yael Rosenberg-Hasson, Saron Araya, Cindy Padilla, Kavita Sarin, Cornelia L. Dekker, Philip Grant, Holden T. Maecker, David Furman, Shai Shen-Orr, Purvesh Khatri, Mark M. Davis
Journal: Cancer Research (2023)

Abstract How the human immune system reacts prior to a cancer diagnosis is largely unknown. Here we analyze a longitudinal cohort of 133 healthy individuals (18 to over 90 years old), 28 of whom developed cancers over nine years. We find the global abundance of a broad spectrum of cytokines (26 out of 32 assayed) surges 2-3 years before cancer diagnosis but not with other conditions (such as inflammatory or cardiovascular diseases). These cytokine surges precede cancer diagnosis only in those 80 years or older, suggesting age-specific inflammatory effects. Meanwhile, in early-stage (but not late-stage) tissues across 10 cancer types, aging elevates cytokine transcriptional activity, which coincides with an age-dependent expansion of the inflammatory macrophage population. We further find that macrophage is a major producer of cytokines in cancer tissues, irrespective of cancer types. These results suggest that cancer associated macrophage is a major source of peripheral inflammatory molecules and may mobilize immunity well before a clinical diagnosis in the elderly. Citation Format: Guangbo Chen, Hong Zheng, Yael Rosenberg-Hasson, Saron Araya, Cindy Padilla, Kavita Sarin, Cornelia L. Dekker, Philip Grant, Holden T. Maecker, David Furman, Shai Shen-Orr, Purvesh Khatri, Mark M. Davis. Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR002.
Abstract A013: Sex-dependent hematopoietic stem cell aging and leukemogenic potential
Authors: WenYong Chen
Journal: Cancer Research (2023)

Abstract Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders. But how HSC aging and sex co-influence leukemogenesis is poorly understood. By examining HSC aging in young, aging (75% lifespan) and longevity (110% lifespan) mice in males vs females, we have discovered that aging males have a significantly higher HSC frequency than females, and that male HSC aging is characterized by an expansion of Lin-CD150+SP HSCs and a decrease of Lin-CD150-SP HSCs, whereas females show opposite HSC changes towards aging and longevity. In line with HSC changes, aging males exhibit an increase of white blood cell counts that is primarily driven by increased myeloid cells, whereas aging females shows a decrease of white blood cell counts that is primarily driven by reduced lymphoid cells. To understand leukemogenic potential of aging HSCs in the true setting of organismal aging, we generated the first aging mouse model of chronic myeloid leukemia (CML) induced by BCR-ABL1 (Oncogene, 2021, 40: 3152-3163). We found that aging male HSCs are significantly more susceptible to BCR-ABL1 transformation and CML induction in aging male mice than aging female HSCs for CML induction in aging female mice. However, in the absence of oncogenic translocation genes, longevity female but not male mice rapidly develop B/myeloid mixed phenotype acute leukemia, a disease of HSC origin, in primary bone marrow transplantation recipients. Leukemias in our aging mouse models phenocopy those of humans in that the incidence of myeloid leukemia is higher in aging men than in women overall, but longevity women have a higher incidence of myeloid leukemia. Using single cell RNA sequencing analysis of HSCs, we found distinct cell clustering patterns and signaling pathways of aging HSCs between male and female mice. The top pathways seen in male HSC aging involve TGFβ and TNFα signaling that have been linked to poor drug response and persistence of human CML stem cells, while those for female HSC aging involve IFNα/γ signaling pathways that have been associated with good drug response of human CML stem cells. Together, our results demonstrate sex-dependent HSC aging and leukemogenic potential and that molecular changes in aging HSCs can inform drug response of leukemia stem cells. Our findings provide novel insight into the etiology of leukemia in males vs females and suggest potential benefit to use sex-based prevention and therapeutic strategies for leukemia in men vs women. Citation Format: WenYong Chen. Sex-dependent hematopoietic stem cell aging and leukemogenic potential [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A013.
Abstract IA003: Neuronal Genome Stability and Plasticity
Authors: Andre Nussenzweig
Journal: Cancer Research (2023)

Abstract The DNA of neurons is continually damaged due to lifelong, high-level metabolic and transcriptional activity. In addition, recent studies have demonstrated extensive “programmed” DNA damage and somatic mutation in differentiating post-mitotic neurons. Here, we identify these endogenous lesions as single strand break intermediates of thymine DNA glycosylase (TDG)-mediated removal of oxidized methylcytosines during active DNA demethylation. Interrupting active DNA demethylation using anti-neoplastic cytosine analogs triggers TDG-dependent neuronal cell death. This suggests that the well-known neurotoxic side effects of certain chemotherapies, also called “chemobrain,” could be linked to DNA repair processes intrinsic to normal neuronal differentiation. In this presentation, we discuss the implications of these findings to neurodegeneration and cancer. Citation Format: Andre Nussenzweig. Neuronal Genome Stability and Plasticity [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA003.
Abstract IA022: Age-induced metabolic reprogramming: A bridge between the aging process and tumorigenesis
Authors: Ana P. Gomes
Journal: Cancer Research (2023)

Abstract Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, chemotherapies remain the standard of care for the majority of lung cancer patients. However, many patients do not respond to these treatments or relapse following an initial response. We postulate that part of the problem is the lack of consideration in preclinical research and clinical trials of the main driver of lung tumorigenesis, the aging process. Here, we show that the organismal metabolic reprogramming that occurs with aging endows cancer cells with pro-aggressive properties favoring progression into metastatic disease through, at least in part, the accumulation in the circulation of methylmalonic acid, a by-product of vitamin B12 deficiency. On the other hand, we also show that this age-induced organismal metabolic reprogramming makes lung tumors intrinsically more resistant to chemotherapies through the chronic upregulation of glucocorticoid hormones. Together, our work demonstrates a role for age-induced systemic metabolic reprogramming in shaping the tumorigenic process toward more aggressive, treatment-resistant disease and offers a rationale for using interventions that ameliorate the metabolic deregulation that occurs with age in the treatment of age-related cancers. Citation Format: Ana P. Gomes. Age-induced metabolic reprogramming: A bridge between the aging process and tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA022.
Abstract A003: Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility
Authors: Masaru Miyano, Rosalyn W. Sayaman, Parijat Senapati, Stefan Hinz, Victoria E. Seewaldt, Dustin Schones, Mark A. LaBarge
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR006) of the Conference Proceedings. Citation Format: Masaru Miyano, Rosalyn W. Sayaman, Parijat Senapati, Stefan Hinz, Victoria E. Seewaldt, Dustin Schones, Mark A. LaBarge. Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A003.
Abstract B008: Autoimmune disease and the risk of anal cancer in the U.S. elderly population
Authors: Minkyo Song, Eric A. Engels, Megan A. Clarke, Aimée R. Kreimer, Meredith S. Shiels
Journal: Cancer Research (2023)

Abstract Background: Recently, anal squamous cell carcinoma (SCC) has increased rapidly over time, particularly among older women. As immunosuppression is associated with increased anal cancer risk, a parallel increase in autoimmune conditions may be contributing to this rising trend. Methods: We conducted a population-based case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (years 2000-2017). Cases were individuals with first anal SCC diagnosed in SEER registries (N=4,505) and 199,566 cancer-free controls from a 5% random sample of Medicare beneficiaries. Using logistic regression, we calculated odds ratios (OR) and 95% confidence intervals (95%CI) for associations with 47 autoimmune conditions identified via Medicare claims. Models were adjusted for age (continuous), sex, race (white, others), year of selection (quartiles), average number of physician claims per year (quartiles), medicare coverage months (quartiles) and smoking status. The false discovery rate was used to correct for multiple comparisons. Results: 18% of cases and 15% of controls had any autoimmune condition diagnosed. Having any autoimmune condition was associated with an increased risk of anal SCC (OR 1.12, 95%CI 1.03-1.22). The strongest risk estimates were for sarcoidosis (OR 1.97, 95%CI 1.22-3.19), followed by systemic lupus erythematosus (1.86, 1.38-2.52) and psoriasis (1.31, 1.08-1.58). Stratified by sex, only women showed significant associations for systemic lupus erythematosus (OR 2.05, 95%CI 1.51-2.78) and men with psoriasis (1.72, 1.25-2.35) and polymyalgia rheumatica (0.33, 0.12-0.89). Conclusion: To date, this is the largest study of anal SCC exploring its association with autoimmunity, especially in this understudied old population. We report a weak to moderately increased risk of certain autoimmune diseases with anal SCC. Some associations differed by sex. Impact/Significance: Understanding the mechanism by which autoimmune diseases increase cancer anal cancer risk may guide better prevention and treatment strategies. Given the rarity of these conditions and their moderate associations with anal cancer, clinical diagnosis of autoimmune diseases cannot explain the rising trend in anal cancer. Future studies are warranted in addressing the underdiagnosis of these autoimmune conditions to better quantify the burden. Citation Format: Minkyo Song, Eric A. Engels, Megan A. Clarke, Aimée R. Kreimer, Meredith S. Shiels. Autoimmune disease and the risk of anal cancer in the U.S. elderly population [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B008.
Abstract A002: Physical and metabolic aspects of therapy induced senescence and polyploidy in an evolving tumor microenvironment
Authors: Michelle R. Dawson, Deepraj Ghosh
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR007) of the Conference Proceedings. Citation Format: Michelle R. Dawson, Deepraj Ghosh. Physical and metabolic aspects of therapy induced senescence and polyploidy in an evolving tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A002.
Abstract B009: A liver-tropic BCL-xL PROTAC effectively clears senescent hepatocytes and prevents NASH-driven HCC in mice
Authors: Yang Yang, Natacha Jn-Simon, Wanyi Hu, Peiyi Zhang, Guangrong Zheng, Liya Pi, Yonghan He, Daohong Zhou
Journal: Cancer Research (2023)

Abstract Accumulation of senescent cells (SnCs) plays a causative role in many age-related diseases and has been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Senolytics that can selectively kill SnCs have the potential to be developed as therapeutics for these diseases. Here we reported the discovery of 753b, a BCL-xL proteolysis targeting chimera (PROTAC), as a potent and liver-tropic senolytic. We found that 753b can selectively clear senescent hepatocytes in aged mice and the STAM mice even though it can potently kill various SnCs in vitro. This is in part because 753b is enriched in the liver after its administration by ip injection. Moreover, 753b treatment can effectively reduce the development of non-alcoholic steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma (HCC) in the STAM mice. These findings suggest that 753b has the potential to be developed as a novel therapeutic for NAFLD and NASH-driven HCC. Citation Format: Yang Yang, Natacha Jn-Simon, Wanyi Hu, Peiyi Zhang, Guangrong Zheng, Liya Pi, Yonghan He, Daohong Zhou. A liver-tropic BCL-xL PROTAC effectively clears senescent hepatocytes and prevents NASH-driven HCC in mice [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B009.
Abstract A021: Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC
Authors: Daniel Spakowicz, Rebecca Hoyd, Caroline E. Wheeler, Nyelia Williams, Amna Bibi, Marium Husain, Srichandhana Rajamouli, Shankar Suman, Joseph Amann, Madison Grogan, Pooja Vibhakar, Dwight H. Owen, David P. Carbone, Ashley Rosko, Christin E. Burd, Carolyn J. Presley
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR004) of the Conference Proceedings. Citation Format: Daniel Spakowicz, Rebecca Hoyd, Caroline E. Wheeler, Nyelia Williams, Amna Bibi, Marium Husain, Srichandhana Rajamouli, Shankar Suman, Joseph Amann, Madison Grogan, Pooja Vibhakar, Dwight H. Owen, David P. Carbone, Ashley Rosko, Christin E. Burd, Carolyn J. Presley. Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A021.